Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Cutaneous lymphoproliferative disorders: Back to the future.

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan-T-cell antigens and clonal T-cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T-cell proliferations, and monotypic immunoglobulin light-chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B-cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T-cell lymphoma (PCSM-TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T-cell or B-cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low-grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease-specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low-grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM-TCL as primary cutaneous CD4+ small/medium T-cell LPD and primary cutaneous acral CD8+ T-cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term "primary cutaneous marginal zone LPD," in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare variant of cutaneous T-cell lymphoma with an aggressive clinical course and a very poor prognosis. Until now, neither a systematic characterization of genetic alterations driving pcAECyTCL has been performed, nor effective therapeutic regimes for patients have been defined. Here, we present the first highresolution genetic characterization of pcAECyTCL by using wholegenome and RNA sequencing. Our study provides a comprehensive description of genetic alterations (i.e., genomic rearrangements, copy number alterations and small-scale mutations) with pathogenic relevance in this lymphoma, including events that recurrently impact genes with important roles in the cell cycle, chromatin regulation and the JAKSTAT pathway. In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL. In line with the genomic data, transcriptome analysis uncovered upregulation of the cell cycle, JAK2 signaling, NF-κB signaling and a high inflammatory response in this cancer. Functional studies confirmed oncogenicity of JAK2 fusions identified in pcAECyTCL and their sensitivity to JAK inhibitor treatment. Our findings strongly suggest that overactive JAK2 signaling is a central driver of pcAECyTCL, and consequently, patients with this neoplasm would likely benefit from therapy with JAK2 inhibitors such as Food and Drug Adminstration-approved ruxolitinib.

Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.

Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSF8, small-scale mutations in LRP1B, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first-line skin-directed therapies or with extracutaneous disease.

Clinical, histopathological and prognostic features of primary cutaneous acral CD8+ T-cell lymphoma and other dermal CD8+ cutaneous lymphoproliferations: results of an EORTC Cutaneous Lymphoma Group workshop.

BACKGROUND: The differential diagnosis of atypical dermal nonepidermotropic CD8+ lymphocytic infiltrates includes a heterogeneous spectrum of lymphoproliferations with overlapping histological and phenotypic features, but divergent clinical manifestations and prognoses. As these neoplasms are rare, more data on their clinicopathological presentation and course are needed. OBJECTIVES: To assess the clinical, histological and immunophenotypic features; outcomes of; and differences between dermal CD8+ lymphoproliferations. METHODS: Retrospective analysis of a series of 46 patients and biopsies by the international EORTC Cutaneous Lymphoma Group. RESULTS: The dermal CD8+ lymphoproliferations (n = 46) could be assigned to one of three groups: (i) cutaneous acral CD8+ T-cell lymphoma (n = 31), characterized mostly by a solitary nodule arising at acral sites, a monotonous dermal infiltrate of small-to-medium-sized CD8+ lymphocytes with a characteristic dot-like pattern of CD68, a low proliferation rate and an excellent prognosis; (ii) primary cutaneous CD8+ peripheral T-cell lymphoma, unspecified/NOS (n = 11), presenting with one or multiple rapidly evolving tumours, mostly medium-sized pleomorphic CD8+ tumour cells with expression of several cytotoxic markers, and high proliferative activity; and (iii) cutaneous CD8+ lymphoproliferations (n = 4), associated with congenital immunodeficiency syndromes in two patients with persisting localized or disseminated violaceous to brownish plaques on the extremities, a histiocyte-rich infiltrate of mostly small CD8+ lymphocytes with subtle atypia and a protracted course; and papular CD8+ eruptions in two patients with acquired immunosuppression. CONCLUSIONS: A constellation of distinct clinical, histopathological and phenotypic features allows discrimination and assignment of dermal CD8+ infiltrates into distinct disease entities. Primary cutaneous acral CD8+ lymphoma, assigned a provisional category in current lymphoma classifications, is a distinct and reproducible entity. A correct diagnosis is essential to avoid unnecessarily aggressive treatment for indolent CD8+ lymphoproliferations and to identify cases with underlying immuno-deficiency or potential for dismal outcome.

The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.

Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8+ T-cell lymphoma and Epstein-Barr virus positive (EBV+) mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added. The term "primary cutaneous CD4+ small/medium T-cell lymphoma" was modified to "primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder" because of its indolent clinical behavior and uncertain malignant potential. Modifications have also been made in the sections on lymphomatoid papulosis, increasing the spectrum of histologic and genetic types, and primary cutaneous marginal zone lymphomas recognizing 2 different subtypes. Herein, the characteristic features of these new and modified entities as well as the results of recent molecular studies with diagnostic, prognostic, and/or therapeutic significance for the different types of primary cutaneous lymphomas are reviewed. An update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

Whole-genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent genetic defects (eg, single nucleotide changes, indels, large chromosomal aberrations) have been identified in BPDCN, none are disease-specific, and more importantly, none explain its genesis or clinical behavior. In this study, we performed the first high resolution whole-genome analysis of BPDCN with a special focus on structural genomic alterations by using whole-genome sequencing and RNA sequencing. Our study, the first to characterize the landscape of genomic rearrangements and copy number alterations of BPDCN at nucleotide-level resolution, revealed that IKZF1, a gene encoding a transcription factor required for the differentiation of plasmacytoid dendritic cell precursors, is focally inactivated through recurrent structural alterations in this neoplasm. In concordance with the genomic data, transcriptome analysis revealed that conserved IKZF1 target genes display a loss-of-IKZF1 expression pattern. Furthermore, up-regulation of cellular processes responsible for cell-cell and cell-ECM interactions, which is a hallmark of IKZF1 deficiency, was prominent in BPDCN. Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients.

Plaque stage folliculotropic mycosis fungoides: histopathologic features and prognostic factors in a series of 40 patients.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides. Recent studies recognized indolent and aggressive subgroups of FMF, but there is controversy how patients presenting with plaques should be classified. The present study describes the histopathologic features of 40 FMF plaques. The aim of the study was to identify risk factors for disease progression and poor outcome in this group. METHODS: Clinical, histopathological, and immunophenotypical data from 40 patients with plaque stage FMF were reviewed and analysed for risk factors for disease progression and survival. RESULTS: After a median follow-up of 80 months, disease progression occurred in 20 of 40 patients. Percentage of atypical cells, cell size, percentage of Ki-67+ cells, and co-existent interfollicular epidermotropism, but not the extent of perifollicular infiltrates, were associated with disease progression and reduced survival, while extensive follicular mucinosis was associated with increased survival. CONCLUSIONS: This study underlines that FMF patients presenting with plaques represent a heterogeneous group and that a subgroup of these patients may have an indolent clinical course. It further shows that histological examination is a valuable tool to differentiate between indolent and aggressive disease.

Array-based CGH of primary cutaneous CD8+ aggressive EPIDERMO-tropic cytotoxic T-cell lymphoma.

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array-comparative genomic hybridization (a-CGH). a-CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A-CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T-cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised.

Genomic analysis reveals recurrent deletion of JAK-STAT signaling inhibitors HNRNPK and SOCS1 in mycosis fungoides.

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL). Causative genetic alterations in MF are unknown. The low recurrence of pathogenic small-scale mutations (ie, nucleotide substitutions, indels) in the disease, calls for the study of additional aspects of MF genetics. Here, we investigated structural genomic alterations in tumor-stage MF by integrating whole-genome sequencing and RNA-sequencing. Multiple genes with roles in cell physiology (n = 113) and metabolism (n = 92) were found to be impacted by genomic rearrangements, including 47 genes currently implicated in cancer. Fusion transcripts involving genes of interest such as DOT1L, KDM6A, LIFR, TP53, and TP63 were also observed. Additionally, we identified recurrent deletions of genes involved in cell cycle control, chromatin regulation, the JAK-STAT pathway, and the PI-3-K pathway. Remarkably, many of these deletions result from genomic rearrangements. Deletion of tumor suppressors HNRNPK and SOCS1 were the most frequent genetic alterations in MF after deletion of CDKN2A. Notably, SOCS1 deletion could be detected in early-stage MF. In agreement with the observed genomic alterations, transcriptome analysis revealed up-regulation of the cell cycle, JAK-STAT, PI-3-K and developmental pathways. Our results position inactivation of HNRNPK and SOCS1 as potential driver events in MF development.

Folliculotropic mycosis fungoides presenting with a solitary lesion: Clinicopathological features and long-term follow-up data in a series of 9 cases.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides, which in rare cases may present with a solitary lesion. Reported cases describe an excellent prognosis, but follow up was generally short. Herein, clinicopathologic characteristics, long-term follow-up data of 9 patients with solitary FMF are presented and differential diagnosis is discussed. METHODS: From a cohort of 203 patients with FMF, 9 cases with solitary FMF were selected. Clinical data and histological sections obtained at diagnosis and during follow up were reviewed. RESULTS: Skin lesions, in all patients located on the head, went into complete remission after treatment with radiotherapy (6 cases) or topical steroids (1 case) or regressed spontaneously (2 cases). After a median follow up of 89 months (range 51-203 months), 5 patients were still in complete remission, 2 patients had developed multiple skin relapses, while 2 patients had progressed to extracutaneous and fatal disease. Histologically, all patients showed marked folliculotropism, associated with syringotropism (4 cases) and/or follicular mucinosis (5 cases). Large-cell transformation was observed at presentation (2 cases) and during follow-up (3 cases). CONCLUSIONS: Long-term follow-up data indicate that patients with solitary FMF do not always have an indolent clinical course and therefore require long-term follow up.

Mycosis fungoides variants-clinicopathologic features, differential diagnosis, and treatment.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, which typically presents with erythematous patches and plaques, histopathologically characterized by superficial infiltrates of small to mediumsized atypical epidermotropic T cells. Apart from this classic type of MF, many clinical and/or histopathologic variants have been described. Correct diagnosis of these MF variants is important, but may be difficult, because they may mimic a wide variety of inflammatory skin diseases. In this review, clinical and histopathologic characteristics of distinct variants of MF are presented, and their differential diagnosis and therapeutic options are discussed.

p16 immunostaining in keratinocytic neoplasia in organ transplant recipients: Bowen's disease shows a characteristic pattern.

BACKGROUND: For selecting therapy, it is important to distinguish different types of keratinocytic neoplasia. It is sometimes difficult to make histopathologic diagnosis, especially in organ transplant recipients (OTR) who develop numerous lesions. METHODS: To investigate p16 immunostaining in different types of keratinocytic neoplasia in OTR, we studied 59 actinic keratoses (AK), 51 Bowen' s disease (BD), 63 squamous cell carcinomas (SCC), 16 benign keratotic lesions (BKL) from 31 OTR patients and 25 controls (eczema and psoriasis). Tissue sections were stained for H&E and p16. We scored intensity, proportion and distribution of p16 positive lesional cells. RESULTS: In 19% of AK, 92% of BD, 35% of SCC and 12% of BKL more than 15% of lesional cells were p16-positive. In 16% of AK, 80% of BD, 18% of SCC and 13% of BKL strong p16 staining was observed. BKL, AK and SCC showed focal and patchy staining, BD showed diffuse pattern with strong staining of all atypical cells. Sparing of the basal layer was predominantly seen in BD. No control specimen showed p16-overexpression. CONCLUSIONS: p16 immunostaining shows a characteristic pattern in BD, but not in AK, SCC and BKL. It appears useful in recognizing BD, but not in differentiating between other keratinocytic neoplasia.

Cutaneous lymphomas with a panniculitic presentation.

Subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous gamma/delta T-cell lymphoma are the two most common types of cutaneous T-cell lymphoma presenting with panniculitis-like lesions. In this article the characteristic clinical, histological and immunophenotypical features of these conditions are reviewed and criteria to differentiate these tumors from other benign and malignant lymphoproliferations presenting with panniculitis-like lesions are discussed.

Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report of an EORTC Cutaneous Lymphoma Task Force Workshop.

AIMS: Aggressive epidermotropic cutaneous CD8(+) lymphoma is currently afforded provisional status in the WHO classification of lymphomas. An EORTC Workshop was convened to describe in detail the features of this putative neoplasm and evaluate its nosological status with respect to other cutaneous CD8(+) lymphomas. METHODS AND RESULTS: Sixty-one CD8(+) cases were analysed at the workshop; clinical details, often with photographs, histological sections, immunohistochemical results, treatment and patient outcome were discussed and recorded. Eighteen cases had distinct features and conformed to the diagnosis of aggressive epidermotropic cutaneous CD8(+) lymphoma. The patients typically present with widespread plaques and tumours, often ulcerated and haemorrhagic, and histologically have striking pagetoid epidermotrophism. A CD8(+) /CD45RA(+) /CD45RO(-) /CD2(-) /CD5(-) /CD56(-) phenotype, with one or more cytotoxic markers, was found in seven of 18 patients, with a very similar phenotype in the remainder. The tumours seldom involve lymph nodes, but mucosal and central nervous system involvement are not uncommon. The prognosis is poor, with a median survival of 12 months. Examples of CD8(+) mycosis fungoides, lymphomatoid papulosis and Woringer-Kolopp disease presented the typical features well documented in the CD4(+) forms of those diseases. CONCLUSIONS: Aggressive epidermotropic cutaneous CD8(+) lymphoma is a distinct lymphoma that warrants inclusion as a distinct entity in future revisions of lymphoma classifications.

Differential expression of TOX by skin-infiltrating T cells in Sézary syndrome and erythrodermic dermatitis.

BACKGROUND: The histopathologic differentiation between Sézary syndrome (SS) and erythrodermic dermatitis may be extremely difficult. In this immunohistochemical study, it was investigated if thymocyte selection-associated high mobility group box protein (TOX) and C-MYC can be used as additional diagnostic markers to differentiate between SS and erythrodermic dermatitis. METHOD: Paraffin-embedded skin biopsies from 15 SS patients and 17 erythrodermic dermatitis patients were stained and scored for TOX or C-MYC expression. RESULTS: Strong nuclear staining for TOX in more than 50% of skin-infiltrating T cells was observed in 13 of 15 (87%) SS cases, whereas erythrodermic dermatitis cases showed weak nuclear staining in 11-50% (median: 25%) of the T cells; strong nuclear staining as found in SS was never observed in erythrodermic dermatitis. No significant differences in C-MYC expression between SS and erythrodermic dermatitis were found. In most patients of both groups, percentages of C-MYC positive-cells varied between less than 10 and 25% of skin-infiltrating T cells. CONCLUSION: Our results suggest that strong expression of TOX in more than 50% of skin-infiltrating T cells in erythrodermic skin is a useful marker in the differentiation between SS and erythrodermic dermatitis, whereas staining for C-MYC does not contribute to differential diagnosis.

Tumor-stage mycosis fungoides of the vulva successfully treated with local low-dose radiotherapy.

Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma. According to the proposed guidelines for MF, skin-directed therapies are the treatment of choice for patients with limited stage disease. We present a case of early-stage MF, who progressed to tumor-stage MF during the postpartum period, showing a solitary ulcerated tumor on the vulva, which was successfully treated with local response-based, low-dose radiotherapy.

Recent advances in primary cutaneous B-cell lymphomas.

PURPOSE OF REVIEW: In the last decade, there has been considerable debate regarding the classification and terminology of the group of primary cutaneous B-cell lymphomas (CBCLs). With the introduction of the WHO-EORTC classification for cutaneous lymphomas, three main types of CBCLs are recognized: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL) and primary cutaneous large B-cell lymphoma, leg type (PCLBCL, LT). RECENT FINDINGS: Epidemiological studies performed on different patient cohorts showed that the CBCL entities described in the WHO-EORTC classification and the 4th WHO classification of tumours of haematopoietic and lymphoid tissues are reproducible worldwide and are clinically relevant, thereby illustrating the clinical usefulness of the WHO-EORTC classification. Furthermore, collaborative studies between the ISCL and EORTC lymphoma group resulted in recommended staging procedures and consensus treatment recommendations for different CBCL subtypes. SUMMARY: The advances in the classification, staging procedures and treatment of CBCLs have led to a major improvement in clinical care. The progress in CBCL classification enables molecular studies on well defined groups of patients and facilitates comparison of treatment results between different centres. Recent studies found that intralesional/intravenous rituximab has a therapeutic value in PCFCL and PCMZL with widespread cutaneous lesions and suggest that therapies targeting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway could be helpful in DLBCL, LT.